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Endocrine Reviews Oct 2018Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits... (Review)
Review
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first-generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.
Topics: Animals; Humans; Inflammation; Lipid Metabolism; Liver; PPAR alpha
PubMed: 30020428
DOI: 10.1210/er.2018-00064 -
Journal of Hepatology Mar 2015Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor belonging, together with PPARγ and PPARβ/δ, to the NR1C nuclear... (Review)
Review
Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor belonging, together with PPARγ and PPARβ/δ, to the NR1C nuclear receptor subfamily. Many PPARα target genes are involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARα activation, in combination with PPARβ/δ agonism, improves steatosis, inflammation and fibrosis in pre-clinical models of non-alcoholic fatty liver disease, identifying a new potential therapeutic area. In this review, we discuss the transcriptional activation and repression mechanisms by PPARα, the spectrum of target genes and chromatin-binding maps from recent genome-wide studies, paying particular attention to PPARα-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response. The role of PPARα, together with other PPARs, in non-alcoholic steatohepatitis will be discussed in light of available pre-clinical and clinical data.
Topics: Animals; Disease Models, Animal; Humans; Inflammation; Lipid Metabolism; Lipogenesis; Liver Cirrhosis; Mice; Models, Statistical; Non-alcoholic Fatty Liver Disease; PPAR alpha
PubMed: 25450203
DOI: 10.1016/j.jhep.2014.10.039 -
Neurochemical Research May 2020Peroxisome proliferator activated receptor alpha (PPAR-α) belongs to the family of ligand-regulated nuclear receptors (PPARs). These receptors after heterodimerization... (Review)
Review
Peroxisome proliferator activated receptor alpha (PPAR-α) belongs to the family of ligand-regulated nuclear receptors (PPARs). These receptors after heterodimerization with retinoid X receptor (RXR) bind in promotor of target genes to PPAR response elements (PPREs) and act as a potent transcription factors. PPAR-α and other receptors from this family, such as PPAR-β/δ and PPAR-γ are expressed in the brain and other organs and play a significant role in oxidative stress, energy homeostasis, mitochondrial fatty acids metabolism and inflammation. PPAR-α takes part in regulation of genes coding proteins that are involved in glutamate homeostasis and cholinergic/dopaminergic signaling in the brain. Moreover, PPAR-α regulates expression of genes coding enzymes engaged in amyloid precursor protein (APP) metabolism. It activates gene coding of α secretase, which is responsible for non-amyloidogenic pathway of APP degradation. It also down regulates β secretase (BACE-1), the main enzyme responsible for amyloid beta (Aβ) peptide release in Alzheimer Diseases (AD). In AD brain expression of genes of PPAR-α and PPAR-γ coactivator-1 alpha (PGC-1α) is significantly decreased. PPARs are altered not only in AD but in other neurodegenerative/neurodevelopmental and psychiatric disorder. PPAR-α downregulation may decrease anti-oxidative and anti-inflammatory processes and could be responsible for the alteration of fatty acid transport, lipid metabolism and disturbances of mitochondria function in the brain of AD patients. Specific activators of PPAR-α may be important for improvement of brain cells metabolism and cognitive function in neurodegenerative and neurodevelopmental disorders.
Topics: Alzheimer Disease; Animals; Brain; Drug Delivery Systems; Fenofibrate; Humans; Neurodegenerative Diseases; PPAR alpha
PubMed: 32170673
DOI: 10.1007/s11064-020-02993-5 -
Nature Metabolism Aug 2022Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients...
Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography-mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.
Topics: Alkanesulfonates; Animals; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Male; Mice; Obesity; PPAR alpha; Phenylpropionates
PubMed: 35995995
DOI: 10.1038/s42255-022-00617-6 -
ELife Dec 2021Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors...
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear.
METHODS
Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that specifically targets mimic and anti- were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high-fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by and the synergic effect of combination of fenofibrate with anti- in NAFLD mouse model.
RESULTS
We revealed that specifically targets through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, significantly reduced FA oxidation and mitochondrial biogenesis by targeting . In -introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti- exhibited the synergic effect on improvement of NAFLD in MCD-fed mice.
CONCLUSIONS
Taken together, our results demonstrate that the novel targets , plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD.
FUNDING
This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940, 2016M3C9A394589324), and the Future-leading Project Research Fund (1.210034.01) of UNIST.
Topics: Animals; Female; Fenofibrate; Humans; Hypolipidemic Agents; Lipid Metabolism; Male; Mice; MicroRNAs; Non-alcoholic Fatty Liver Disease; PPAR alpha
PubMed: 34964438
DOI: 10.7554/eLife.70472 -
International Journal of Molecular... Aug 2021In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty... (Review)
Review
In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal β-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid β-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid β-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients.
Topics: Acyl-CoA Oxidase; Animals; Fatty Acids; Humans; Liver; Oxidation-Reduction; Oxidoreductases; PPAR alpha; Peroxisome Proliferators; Peroxisomes; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Response Elements; Retinoid X Receptors; Transcriptional Activation
PubMed: 34445672
DOI: 10.3390/ijms22168969 -
Cell Metabolism Sep 2017Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated...
Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies downregulation of insulin, protein synthesis, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, upregulation of PPARα target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice.
Topics: Aging; Animals; Diet, High-Fat; Diet, Ketogenic; Fasting; Gene Expression Regulation; Liver; Male; Memory; Mice, Inbred C57BL; Mortality; PPAR alpha
PubMed: 28877458
DOI: 10.1016/j.cmet.2017.08.004 -
Journal of the American Society of... Apr 2018Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys...
Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys show significantly increased fibrosis with impaired kidney function, the mechanisms underlying the effects of aging on renal fibrosis have not been investigated. In this study, we investigated peroxisome proliferator-activated receptor (PPAR) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPAR and the FAO pathway-associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPAR protein expression associated with increased expression of PPAR-targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPAR expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF--induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPAR mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPAR signaling during aging aggravates renal fibrosis development, and targeting PPAR is useful for preventing age-associated CKD.
Topics: Aging; Animals; Caloric Restriction; Cell Line; Epithelial Cells; Extracellular Matrix Proteins; Fatty Acids; Fibrosis; Gene Expression Regulation; Kidney; Mice; Mice, Knockout; MicroRNAs; Oleic Acid; Oxidation-Reduction; PPAR alpha; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta
PubMed: 29440279
DOI: 10.1681/ASN.2017070802 -
Proceedings of the National Academy of... Mar 2023Diabetes can result in impaired corneal wound healing. Mitochondrial dysfunction plays an important role in diabetic complications. However, the regulation of...
Diabetes can result in impaired corneal wound healing. Mitochondrial dysfunction plays an important role in diabetic complications. However, the regulation of mitochondria function in the diabetic cornea and its impacts on wound healing remain elusive. The present study aimed to explore the molecular basis for the disturbed mitochondrial metabolism and subsequent wound healing impairment in the diabetic cornea. Seahorse analysis showed that mitochondrial oxidative phosphorylation is a major source of ATP production in human corneal epithelial cells. Live corneal biopsy punches from type 1 and type 2 diabetic mouse models showed impaired mitochondrial functions, correlating with impaired corneal wound healing, compared to nondiabetic controls. To approach the molecular basis for the impaired mitochondrial function, we found that Peroxisome Proliferator-Activated Receptor-α (PPARα) expression was downregulated in diabetic human corneas. Even without diabetes, global knockout mice and corneal epithelium-specific conditional knockout mice showed disturbed mitochondrial function and delayed wound healing in the cornea, similar to that in diabetic corneas. In contrast, fenofibrate, a PPARα agonist, ameliorated mitochondrial dysfunction and enhanced wound healing in the corneas of diabetic mice. Similarly, corneal epithelium-specific transgenic overexpression improved mitochondrial function and enhanced wound healing in the cornea. Furthermore, PPARα agonist ameliorated the mitochondrial dysfunction in primary human corneal epithelial cells exposed to diabetic stressors, which was impeded by siRNA knockdown of , suggesting a PPARα-dependent mechanism. These findings suggest that downregulation of PPARα plays an important role in the impaired mitochondrial function in the corneal epithelium and delayed corneal wound healing in diabetes.
Topics: Mice; Humans; Animals; PPAR alpha; Diabetes Mellitus, Experimental; Cornea; Wound Healing; Mice, Knockout; Mitochondria
PubMed: 36943878
DOI: 10.1073/pnas.2217576120 -
British Journal of Pharmacology Nov 2018Nuciferine, an alkaloid found in Nelumbo nucifera leaves, alleviates dyslipidemia in vivo. However, whether it improves liver injury in diabetic conditions and the...
BACKGROUND AND PURPOSE
Nuciferine, an alkaloid found in Nelumbo nucifera leaves, alleviates dyslipidemia in vivo. However, whether it improves liver injury in diabetic conditions and the underlying mechanism is unclear. The present study aimed to investigate the effects of nuciferine on lipid and glucose metabolism in a murine model of Type 2 diabetes mellitus (T2DM) and to determine the underlying mechanisms of these effects.
EXPERIMENTAL APPROACH
A murine model of T2DM was induced by high-fat diet (HFD) feeding combined with streptozocin (STZ) injections, and the diabetic mice were treated with nuciferine in their food. The underlying mechanism of the anti-steatotic effect of nuciferine was further explored in HepG2 hepatocytes cultured with palmitic acid. Major signalling profiles involved in fatty acid oxidation were then evaluated, using Western blot, RT-qPCR and si-RNA techniques, along with immunohistochemistry.
KEY RESULTS
Nuciferine restored impaired glucose tolerance and insulin resistance in diabetic mice. Hepatic levels of total cholesterol, triglycerides and LDL were decreased, as were the number of lipid droplets, by nuciferine treatment. Furthermore, nuciferine up-regulated β-oxidation related genes in livers of diabetic mice. Luciferase reporter cell assay showed that nuciferine directly reversed palmitic acid-induced inhibition of PPARα transcriptional activity. Silencing PPARγ coactivator-1α (PGC1α) expression in HepG2 cells abolished the effects of nuciferine in accelerating β-oxidation.
CONCLUSIONS AND IMPLICATIONS
Nuciferine improved lipid profile and attenuated hepatic steatosis in HFD/STZ-induced diabetic mice by activating the PPARα/PGC1α pathway. Nuciferine may be a potentially important candidate in improving hepatic steatosis and the management of T2DM.
Topics: Animals; Aporphines; Diabetes Mellitus, Experimental; Diet, High-Fat; Fatty Liver; Glucose Tolerance Test; Hep G2 Cells; Humans; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; PPAR alpha; Streptozocin; Transcription Factors
PubMed: 30129056
DOI: 10.1111/bph.14482